ATP (adenosine triphosphate, hereinafter sometimes simply referred to as ATP) is the most important compound that stores energy of living organisms and supplies the energy when necessary, and it is considered that ATP reduction is related to pathological conditions of various diseases. For example, with regard to the causes of various types of hereditary hemolytic anemia, ATP reduction in erythrocytes is considered as a mechanism of hemolysis. Examples include sickle cell disease (Non-Patent Document 1), pyruvate kinase deficiency (Non-Patent Document 2), spherocytosis (Non-Patent Document 3), elliptocytosis (Non-Patent Document 3), stomatocytosis (Non-Patent Document 4), thalassemia (Non-Patent Document 5), etc.
Additionally, intracellular ATP reduction is suggested as a mechanism of myocardial damage due to ischemic heart disease (Non-Patent Document 6), and it is reported that symptoms of chronic stable angina were suppressed by high-dose administration of a xanthine oxidase/xanthine dehydrogenase inhibitor, allopurinol (Non-Patent Document 7). The authors suggested that an increase in ATP due to allopurinol had a favorable effect on ischemic heart disease (Non-Patent Document 7).
Furthermore, an ATP enhancement therapy is likely to be effective for heart failure. Heart failure patients often undergo heart transplantation in US and, instead of a period from occurrence of heart failure to death, a period from occurrence of heart failure to heart transplantation is used as a measure of a speed of progress of heart failure. A short period until heart transplantation indicates that the progress of heart failure is fast. In Europe and US, the frequency of hereditary muscle AMP deaminase (AMPD) deficiency is extremely high, and about 20% of the general population has heterozygous deficiency. It is known from studies that people with muscle genetic AMPD deficiency have a longer period from heart failure to heart transplantation (Non-Patent Document 8). It is also suggested that an AMPD inhibitor improves heart failure in mice (Non-Patent Document 9). Generally, ATP of muscle decreases due to exercise. However, it is reported that people with hereditary muscle AMPD deficiency have intramuscular ATP not decreasing, or restrained from decreasing, after exercise (Non-Patent Document 10). Specifically, since AMP is not converted into IMP (inosine monophosphate, hereinafter sometimes simply referred to as IMP), AMP reduction can be prevented and ATP reduction does not occur (FIG. 1). From above, it is considered that genetic muscle AMPD deficiency was less likely to cause ATP reduction in cardiomyocytes and suppressed the progress of heart failure.
It can be expected that enhancing ATP in this way improves pathological conditions of diseases in which a decrease in ATP relates to the pathological conditions.
Although it is reported that inosine enhances muscular movement in expectation of occurrence of an enhancing action on muscular movement due to ATP increased by administration of inosine, a report denying the effect thereof is also made recently (Non-Patent Document 11). However, it is possible that a cause of inability to prove inosine's muscular enhancing action is because inosine alone is not sufficient for completing the ATP enhancing action.
Nishino et al. have found that a xanthine oxidase/xanthine dehydrogenase inhibitor such as febuxostat administered to a model mouse of amyotrophic lateral sclerosis (hereinafter sometimes simply referred to as ALS) inhibits disease progression (Non-Patent Document 12). Allopurinol did not inhibit the disease progression. Nishino et al. speculate that an increase in ATP of nerve cells due to administration of febuxostat suppresses disease progression (Non-Patent Document 12). Nishino et al. speculate that a reason that allopurinol does not have an effect is because allopurinol consumes PRPP and inhibits ATP synthesis to the contrary (Non-Patent Document 12). In fact, it is reported that knock-down of Na/K-ATPase in ALS model mice suppressed degeneration of nerve cells (Non-Patent Document 12). It is also reported that Na/K-ATPase activity is increased in ALS patients (Non-Patent Document 13). Therefore, it is considered that activation of Na/K-ATPase that reduces ATP promotes the onset or progression of ALS and that suppression of Na/K-ATPase that suppresses ATP reduction suppresses the progress of ALS.
Furthermore, it is reported that administration of inosine alleviates symptoms of Parkinson's disease (Non-Patent Document 14) and multiple sclerosis (Non-Patent Document 15). The authors of both documents believe that a decrease in serum uric acid value may be related to the diseases. Clinical trials are conducted for the purpose of raising the serum uric acid value by administering inosine, and producing a therapeutic effect. However, the effect is not enough in the past reports.
It has been reported that intracellular ATP somewhat increases due to single administration of inosine. In fact, Ogasawara et al. reported that ATP increased when erythrocytes allowed to stand at low temperature for 20 to 30 days and reduced in ATP were allowed to stand for one hour after addition of inosine (Non-Patent Document 16). However, inosine is rapidly metabolized in human bodies through hypoxanthine and xanthine to uric acid (FIG. 1). Therefore, inosine alone was insufficient to produce the sufficient ATP enhancing action. Additionally, although single administration of febuxostat is expected to somewhat enhance intracellular ATP, this alone may be insufficient.